The major objectives of the proposed research are to develop nontraumatic methods with which to study central nervous system (CNS) cholinergic function in man, and to explore the extent of cholinergic involvement in a variety of mental and neurological disease states. Four parallel lines of investigation will be followed: 1. We have shown that one can achieve effective labeling of mouse brain acetylcholine (ACh) and choline (Ch) by supplying deuterium labeled Ch in the diet. Preliminary findings indicate that an excellent correlation exists between the incorporation of Ch in the CNS, brain ACh synthesis, and reflected changes in the Ch pools in plasma and red blood cells (RBC). An extensive protocol has been outlined in this application, aimed at determining the reliability of this animal model, and in establishing to what extent it may be useful in predicting central cholinergic function, using peripheral neurochemical indices from blood. 2. The effect of chronic lithium administration on CNS cholinergic parameters will be determined directly in mice. Levels of Ch and ACh; activity of choline acetyltransferase and acetylcholinesterase; cholinergic receptor binding; turnover rate of ACh; HACht; and effect on dopaminergic and GABA-ergic systems will be studied in specific areas in mouse brains. 3. We will continue to explore the relevance of elevated Ch values which we have found in RBCs of certain depressed patients, in Gilles de la Tourette's syndrome, and in bipolar individuals treated with lithium carbonate. In vivo and in vitro studies are planned, aimed at exploring RBC membrane-related factors which may be responsible for these findings. Laboratory data will be correlated with clinical changes and with sleep-EEG alterations observed in the patients involved. Patients will be studied prior to, as well as during drug treatment with either lithium, amitriptyline, nortriptyline or desmethylimipramine. 4. Studies will be conducted in rats, aimed at a direct analysis of the role that cholinergic mechanisms might play in the initiation and control of sleep REM parameters. The "cholinergic supersensitivity" hypothesis of REM sleep induction, and the effect of various Ch diets on sleep will be explored in these experimental animals.